Multiple myeloma (MM) is the second most prevalent hematological malignancy and remains incurable with a median survival of three to five years. Despite the introduction of several novel drugs and the high efficacy of these drugs shown in vitro, less than 60% of patients respond to therapy upfront, and more than 90% relapse and develop drug resistance. The discrepancy between in vitro efficacy and clinical outcomes can be attributed to several limitations of the classic tissue culture drug screening models including: (1) Most of the in vitro models use MM cell line cultures and neglect the vital role of the bone marrow (BM) microenvironment in MM progression, which promotes drug resistance; (2) The BM niche is a three-dimensional (3D) structure with a gradient of both oxygen and drug concentration as a function of distance from blood vessels. The vascular niche (close to the blood vessels) presents high oxygenation levels, includes more proliferative cells, and receives higher drug concentrations, while the endosteal niche (close to the bone) is hypoxic, receives lower drug concentrations, and includes less proliferative but more drug-resistant cells. The classic two-dimensional (2D) in vitro tissue culture system cannot mimic oxygen and drug gradients in culture wells, making all cells highly oxygenated; therefore, 2D cultures cannot accurately predict drug sensitivity in different parts of the BM niche due to lack of accurate effects throughout various tissue depths; and (3) The MM patient population is highly variable, both genetically and epigenetically, and the biological characteristics of patients are widely different, which demonstrates sensitivity of individual patients to different therapies. Typical 2D models rely on a limited number of MM cell lines which cannot reflect the enormous heterogeneity and variations present in individual patients.
Several 3D MM models were developed based on Matrigel scaffolds, acrylic polymers, and human bone chips. These provide a better alternative compared to 2D cultures; however, each has its limitations. The Matrigel and synthetic polymer-based models are made from materials which are not physiologically found in the BM and may cause significant changes in interactions between different culture components and the matrix. The bone-chip-based model is closer to BM physiological conditions; however, it is technically challenging, as it needs about eight weeks before it is ready for drug testing. Also, it relies on interaction of MM cells with a normal BM microenvironment, which was proven to be significantly different from the MM microenvironment. All together, these three models are based on foreign materials and refer to all MM patients as one group, ignoring inherent heterogeneity. Therefore, a need exists to develop a better model for testing drug efficacy that takes into account these factors.